This invention relates to a process for the production of alkynylated aromatic and heterocyclic compounds, and more specifically to such a process in which the alkynylated compound is produced using an aryl or heterocyclic nitrile as a starting reagent.
A variety of methods have been described for preparation of aromatic or heterocyclic alkynyl compounds. Many of them involve a catalytic reaction in which an aromatic, heterocyclic, or other halide is a reagent. Some others proceed through an intermediate propargyl or other alkynyl alcohol. Still others proceed by different routes.
For example, Zimmer et al., U.S. Pat. No. 5,202,349, disclose (column 9) the production of certain pharmaceutically active substituted phenylacetylenes in which the acetylenic group is further substituted by an aromatic or heterocyclic group, by reaction of a type of substituted phenyl bromide or iodide with an aromatic or heterocyclic acetylene, or of a similar type of substituted phenylacetylene with an aromatic or heterocyclic bromide or iodide, in the presence of a tertiary amine, a palladium complex catalyst, and optionally a catalytic amount of cuprous iodide.
Dieck et al., Organometallic Chem. 93:259 (1975) disclose production of substituted acetylenes by reaction of aryl and vinylic halides with phenylacetylene and three aliphatic alkynes in the presence of palladium acetate catalyst and an amine. Rossi et al., Tetrahedron 40:2773 (1984) disclose production of acetylenes substituted by bithienyl and phenylthienyl groups, by reaction of the corresponding bithienyl or phenylthienyl iodide with trimethylsilylethynyl magnesium bromide, followed by reaction of the thus produced substituted acetylene with, for example, monobromoethylene.
Similarly, in Kirchoff et al., U.S. Pat. No. 4,724,260,1-trimethylsilyl-2-(4-benzocyclobutyl)acetylene was prepared by reaction of trimethylsilylacetylene and 4-bromobenzocyclobutane in the presence of a catalyst, e.g. palladium (II) chloride, triphenylphosphine and cuprous iodide. Aryl alkynes were produced from aryl halides and a terminal alkyne by a generally similar reaction in Zhi et al, U.S. Pat. No. 6,566,372 (col. 67, e.g.). Tegeler et al. U.S. Pat. No. 6,500,849 disclose production of pyridyl aryl alkynes by reaction of a halopyridine with an aryl alkyne (col. 11, e.g.) in the presence of a similar catalyst and an acid acceptor.
Beletskaya et al., Tetrahedron Letters 44:5011 (2003) describe the Sonogashira-Hagihara reaction, a coupling of a terminal acetylene with an aryl iodide in the presence of a nickel catalyst. Sonogashira, J. Organomet. Chem. 653:46 (2002) further describes palladium-copper cross-coupling of terminal acetylenes with halides.
Chandaratna, U.S. Pat. No. 5,264,456, also disclose reaction between an acetylenic compound and a halide, in this case between either a substituted phenylethyne or a zinc salt of such a compound, and a substituted halide, in the presence of cuprous iodide and a palladium complex.
Brunner et al., U.S. Pat. No. 4,508,560, disclose the production of certain herbicidal heterocyclyl/aryl acetylenic compounds by reaction of a phenyl, naphthyl or heterocyclic acetylene with a substituted heterocyclic halide in which the heterocyclic group contains a 5- or 6-membered ring. The same patent also discloses an alternate process for preparing such compounds, in which the substituted heterocyclic halide is reacted with an aryl- or heterocyclic-substituted propargyl alcohol in the presence of a strong base and a metal catalyst. Another patent by Brunner et al., U.S. Pat. No. 4,412,856, discloses similar processes for the production of certain herbicidal diaryl or aryl/heterocyclyl substituted acetylenes.
Another reaction for producing such compounds, namely that involving an aryl compound having a leaving group such as a sulfonate, is disclosed in Babb et al., U.S. Pat. No. 6,252,001.
Reiffenrath et al., U.S. Pat. No. 5,084,204, discloses several processes for the preparation of disubstituted acetylenes. These include (a): brominating and then dehydrohalogenating the corresponding stilbenes; (b) reacting a compound having a methylene-ketonic group in the position where a triple bond is desired with an inorganic acid chloride, followed by dehydrohalogenation; (c) reacting such a compound with semicarbazide and selenium dioxide, followed by warming in the presence of methyllithium; (d) coupling of an aryl zinc compound with an aryl halide; (e) rearrangement of a 1,1-diaryl-2-halogenoethylene; (f) reacting a 4-substituted phenyl- or cyclohexylacetylene with an aryl halide; and (g) adding a hydrogen halide to a cyclohexene derivative.
Benzonitriles are readily available substrates, yet the development of processes for producing substituted alkynyl aromatic compounds has focused primarily, even nearly entirely, on processes for producing such compounds from aryl halides. A process that enables production of such compounds from benzonitriles and other aryl or heterocyclic nitrites would be welcome.